As is well known, Vitamin D.sub.2 (also known as "calciferol") and Vitamin D.sub.3 (also known as "cholecalciferol") are effective in humans as antirachitic nutritional factors Vitamin D.sub.2 is obtainable from ergosterol by uv irradiation in a suitable solvent, and Vitamin D.sub.3 can be obtained by irradiation of its provitamin, 7-dehydrocholesterol. In about the early 1970s, interest developed in 1.alpha.,25-dihydroxycholecalciferol, which is the polar, biologically active, metabolite of Vitamin D.sub.3, due to an extremely rapidly onset of physiological activity A few years later, another new Vitamin D.sub.3 analogue, again with rapid onset of physiological activity, was described by Barton et al (1.alpha.-hydroxy-Vitamin D.sub.3).
Several of these Vitamin D analogues are illustrated by reference to the Formula 1 structure In the case of 1.alpha.,25-dihydroxycholecalciferol, X is hydroxyl as are both R.sub.2 and R.sub.3. For 1.alpha.-hydroxy-Vitamin D.sub.3, X is hydrogen while both R.sub.2 and R.sub.3 are hydroxyl. ##STR3##
The Formula structure can be further generalized (and often is, particularly in description of syntheses) by more generally representing the side chain R' of the Formula 1 representation is a part.
Vitamin D analogue syntheses have received considerable attention, particularly recently, due to evidence that various Vitamin D.sub.3 related compounds are hormonally active and may be clinically useful regulators of various fundamental physiological processes. Thus, for example, 1,25-dihydroxy-Vitamin D.sub.3 has been shown to modulate the immune function of monocytes and macrophages, Huebel et al., "In-vivo Effect of 1,25-dihydroxy Vitamin D.sub.3 on Phagocyte Function in Hemodialysis Patients," Kidney International, 40 (5), pp. 927-933 (1991). Calcipotriol (also known as "MC-903") is an analogue of the physiologically active metabolite of Vitamin D.sub.3, 1.alpha.,25-dihydoxycholecalciferol, which is indicated as efficacious in reducing in hyperproliferation for psoriasis patients by Arnold et al., "Induction of Epidermal Ornithine Decarboxylase Following Tape Stripping is Inhibited by a Topical Vitamin D.sub.3 Analogue MC-903,"British Journal of Dermatology, 125 (1), pp. 6-8 (1991). Binderup et al., "20-Epi-Vitamin D.sub.3 Analogues, A Novel Class of Potent Regulators of Cell Growth and Immune Responses," Biochemical Pharmacology, 42 (8), pp. 1569-1576 (1991), found the 20-Epi-Vitamin D.sub.3 analogues (structurally related to 1.alpha.,25-dihydroxycholecalciferol) to be very potent inhibitors of T-lymphocyte proliferation induced by interleukin-1 or alloantigen. These 20-epi-Vitamin D.sub.3 analogues are characterized by an altered stereochemistry at carbon 20 of the side chain
Thus, various Vitamin D analogues are of potential interest in therapeutic applications, such as the prevention of graft rejections and in the treatment of cancer and auto-immune diseases, as well as in the treatment of psoriasis.
These increasingly interesting potential clinical applications of Vitamin D analogues have enhanced interest in simplifying their syntheses. Two strategies for 1.alpha.-hydroxy-Vitamin D analogues are currently employed. One is based on a biomimetic path from a normal steroid precursor, such as, for example, reported by Barton et al in their 1973 description of the synthesis of 1.alpha.-hydroxy-Vitamin D.sub.3, J. Am. Chem. Soc., 95 (8), pp. 2748-2749 (1973). The other current strategy is based on a convergent approach of attaching a preformed ring A system to a CD fragment (Grundmann ketone or an analogue thereof), such as is illustrated by Posner et al., J. Org. Chem., 55, pp. 3967-3969 (1990).
Accordingly, a simple convergent strategy that can readily be adopted for the synthesis of many Vitamin D analogues, particularly those with differing side chains, would be useful to prepare compounds that are presently clinically useful, as well as analogues for potential clinical uses in this rapidly developing field.